Rheumatoid arthritis (RA) is a chronic, systemic, inflammatory autoimmune disease targeting the synovium, the tissue that lines bone joints, and is associated with increased risk of infection, osteoporosis, and cardiovascular disease. RA causes pain and swelling, leading to irreversible joint damage, severe functional impairment, and premature death. Approximately 1 % of population is affected worldwide with an average of onset between 30 to 50 years of age (in 2002, approximately 2.8 million Americans). RA causes significant personal, social, and economic costs. Despite the therapeutics available, there is no cure for RA. Some patients still have poorly or incompletely controlled disease. Furthermore, the therapeutics currently in use exhibit variable response rates, have been associated with serious side-effects, require subcutaneous administration, and in some cases are extremely expensive. Thus, there is still a great need for the development of a safe, effective treatment for RA. We are developing COG133, a peptide derived from apolipoprotein-E (apoE), which displays potent anti-inflammatory activity in a variety of cell-based and whole animal models of inflammation. COG133 significantly decreased lipopolysaccharide (LPS)-induced TNF-alpha and IL-6 levels in the blood and the brain of mice (Lynch et al. 2003). In addition, COG133 was effective in reducing TNF-alpha release in whole human blood stimulated with LPS. Data with a murine model experimental allergic encephalomyelitis model (EAE) indicated that treatment with COG133 significantly delayed the onset and the severity of symptoms. These data collectively indicate that COG 133 effectively suppresses release of cytokines and free radicals in a number of cell-based and whole animal models of inflammation. In this Phase I proposal, we will perform whole animal and cell-based tests to prove the principle that COG133 can effectively reduce the inflammation, which is the hallmark of RA. Specific Aim 1: Measure the anti- inflammatory activity of COG133 compared to saline and dexamethasone controls in a collagen induced model of rheumatoid arthritis in mice. Specific Aim 2: Measure the anti-inflammatory activity of COG133 compared to saline and dexamethasone controls in stimulated human synovial cell fibroblasts that release IL-6, nitric oxide, matrix metalloproteases (MMPs) and tissue inhibitors of MMPs. Results from these studies will determine if COG133 is a candidate therapy for rheumatoid arthritis. [unreadable] [unreadable]